The long-term objective of this research is to determine the role of the TGFb type III (TGFbRIII) receptor in TGFb-related processes in normal and cancerous growth, particularly in hepatocytes. A conditional knockout of the TbRIII gene will be made using the Cre/lox system. We will create one strain of mice which will carry in the germline the TbRIII gene flanked by the Cre target sequence, lox(P). To make a hepatocyte- specific knockout, these mice will be crossed with transgenic mice in which Cre expression is both hepatocyte-specific and inducible (gift of Prof. Pierre Chambon, IgBMC, France) the knockout phenotype will be assessed by standard histological methods combined with in situ hybridization and immunohistochemistry to assess potential alterations in specific genes (e.g. TGFb- and growth-associated genes). In addition, the level of cell turnover in liver will be assessed by BrdU incorporation and terminal dUTP nick end labeling. The effects of TBRIII deficiency on TGFb-induced changes in growth will be directly examined in vitro in primary cultures of hepatocytes. Finally, in vivo studies will be performed to determine how TbRIII deficiency affects spontaneous and carcinogen-induced liver tumorigenesis.